Obesity, along with its associated complications, constitutes one of the most serious public health concerns of the 21st century. Although causally linked to debilitating conditions such as insulin resistance, type 2 diabetes, atherosclerosis and cardiovascular disease, there remains limited effective therapeutic treatment for obesity. Leptin, an adipose tissue-derived hormone that communicates the status of peripheral energy reserves to the brain has robust influence on appetite suppression and on increasing energy expenditure. These features of leptin initially created great excitement for the treatment of obesity; however the development of leptin resistance in the brains of obese individuals has prevented its use as an effective anti-obesity therapeutic. Despite significant research efforts both in academia and industry, an understanding of the molecular underpinnings of leptin resistance remains elusive. Our initial observations indicate that increased Endoplasmic Reticulum (ER) stress during obesity has a crucial role in the development of leptin resistance, and that a transcription factor called the X-Box binding protein 1 (XBP1) is key for maintaining leptin action in the brain. We have also previously documented that reducing ER stress with chemical chaperones increases leptin sensitivity in the severely obese and leptin resistant mice. Our proposal is based on these previous observations and has three Specific Aims. The first Aim will focus on determining the ER stress-induced alterations in the LepRb-associated protein complexes and investigate whether an inhibitory protein that blocks leptin action is up regulated or a protein that is required for leptin action is down regulated by ER stress. Furthermore, we will also determine whether any post-translational modifications created on LepRb and/or Jak2 by ER stress that reduces their activity. The second aim will use conditional knockout models of XBP1 to delineate the main neuronal population in which XBP1 is mainly required for leptin action. In the final aim of our application, by both using genetic approaches and acute gain-of-function experiments, we will explore the consequences of up regulating ER capacity and reducing ER stress on leptin sensitivity in the brain.